Brain, Heal Thyself

Deprived of our blood-forming stem cells, we would all quickly die. These bone-marrow cells replenish red and white blood cells day in and day out for decades. The skin, liver, gut, and perhaps other organs are also thought to have their own stem cells that replace injured and dead cells. Not so the brain: The conventional wisdom has long been that it doesn’t have stem cells--perhaps in part because it would have a hard time holding on to memories if its cells were constantly being replaced. Instead the brain starts out with more cells than it ordinarily needs in a lifetime. Nature gives you too many brain cells to start with and assumes that you won’t do anything silly like get into a boxing ring or ride a motorcycle without a helmet, says Samuel Weiss, a neuroscientist at the University of Calgary in Canada. And in most cases nature has done well, because most of us don’t need replacement.

Nevertheless, the conventional wisdom on brain stem cells is changing these days. Although no one has yet conclusively isolated stem cells from an adult mammal’s brain, Weiss and other researchers have induced mouse brain cells to act like stem cells in the lab. And they have found good reason to hope that it may one day be possible to get cells in the adult human brain to act like stem cells--and perhaps replace tissue that has been damaged by stroke or by a disease such as Huntington’s or Parkinson’s.

One of the leaders in this new field is Evan Snyder, at Harvard Medical School. In 1992 he announced that he and his colleagues had removed stemlike cells from the brains of newborn mice. Specifically, the cells came from the cerebellum--a motor-coordinating area of the brain that continues developing for a brief postnatal period. These immature cells were amorphous and flat, lacking the long, delicate connecting fibers--the axon and dendrites--of mature neurons. Under normal circumstances these cells would rapidly differentiate into specialized cells and would no longer reproduce themselves. But Snyder infected them with a retrovirus carrying a gene that prompted the cells to divide. Not only did the cells reproduce, they also began spinning off the three main types of mature brain cells: the message-carrying neurons; astrocytes, cells that surround the capillaries, forming the blood-brain barrier; and oligodendrocytes, which make the myelin that insulates neurons.

Although their genesis was somewhat artificial, Snyder claims that his manipulated cells meet the requirements of true stem cells: they can reproduce and maintain themselves, and they can give rise to all the major cell types in the brain. But were they just a laboratory curiosity? To find out, Snyder injected the genetically engineered cells into the brains of newborn mice, with a genetic marker that allowed him to track them. (The marked cells turned blue when exposed to a special stain.) After the mice matured, he killed them and examined their brains.

Snyder found that the marked cells had indeed differentiated into neurons and other brain cells--their destiny dependent on the site at which they had settled--and some had formed normal synaptic connections with existing brain cells. What’s more, after differentiating, the cells had ceased dividing, just as normal brain cells would--possibly because of some innate brain signal that dampens division. To date, Snyder has injected his stemlike cells into more than 1,000 mice without once seeing the uncontrolled cell growth that makes a tumor.

Snyder’s long-term goal, however, was to see whether his implanted cells could repair some kinds of brain damage. And in recent experiments, he has found that they probably can. For example, when he injected the cells into newborn mice with artificially induced stroke, the cells migrated into damaged areas. Some differentiated into neurons and oligodendrocytes, the cells most commonly injured when the oxygen supply is cut off, as it is in a stroke. Snyder thinks that the cells may migrate and mature so readily because they are responding to developmental signals analogous to those that occur in the embryo--growth factors, perhaps, that in this case are put out by dying neurons or their neighbors. Ordinary mature brain cells, he speculates, have lost the ability to respond to such signals, or the signals may somehow be suppressed.

In his latest research, Snyder and his colleagues are using his stem cells to perform a type of gene therapy. They spliced into the cells a gene that codes for an enzyme missing in children with Tay-Sachs disease. This enzyme breaks down a cellular waste product in the brain. Without the enzyme, the waste accumulates in the brains of children with the disease, causing severe mental retardation and death. Snyder found that once inserted into mouse brains, the genetically engineered cells began producing the enzyme at levels thought to be sufficient to alleviate symptoms of the disease in humans. In a brain with Tay-Sachs, he thinks, the stem cells might naturally tend to spread and produce their crucial enzyme throughout the damaged brain.

Weiss, meanwhile, has taken a different approach to cell repair in the brain. He has been working with cells taken from the subependymal layer, at the core of the brain. In mice, this region produces specialized cells that replace worn-out cells in the olfactory bulb, the part of the brain that controls the sense of smell. Weiss has found that by treating subependymal cells with a protein called epidermal growth factor, or egf, the cells, like those in Snyder’s experiments, reproduced both themselves and the three major brain-cell types. Weiss says that both his and Snyder’s approaches promote cell division, his method by an external signal from egf, and Snyder’s from an internal genetic command. More research, he says, will determine which is the more effective strategy. Both, however, take advantage of the fact that actively dividing cells have not yet differentiated into specialized tissue.

Recently, Weiss and his colleagues Constance Craig and Derek van der Kooy of the University of Toronto have found that injection of egf into mouse brains spurred the growth of new neurons. These cells spread into regions near the subependymal layer, including the striatum, which is involved in regulating motor functions. This is significant, because in people with Huntington’s disease, neurons in this region die. Something that I would consider to be very primitive--simply infusing egf--seems to have the potential to replace the neurons that are lost in Huntington’s disease, says Weiss.

For now, the gap between experiments with laboratory mice and human cell therapy for brain damage is enormous. Snyder and Weiss both believe, however, that their experiments show that the human brain has the potential to repair itself, and that it may indeed even have its own stem cells, only in numbers too small to be effective for anything but the repair of tiny injuries. Infusing it with egf might be one way to help it; transplanting cells that have been taken from the brains of human accident victims, and that have been manipulated to become stemlike, might be another.

Sometimes, when the brain is really massively damaged, says Snyder, it tries to evoke these same mechanisms but just can’t quite do it to the extent that you care about. What I take away from this is that the brain wants to repair itself--there are cries for help, so to speak. Now, if we understand the language of those cries, I think we can jump into that breach and help out, either by supplying more of the factors that the brain is making at a low level or additional stem cells to augment the brain’s own supply.